APPLICANT'S ABSTRACT: This application is a competing renewal for an institutional research training program on "Genetic Aspects of Alcoholism." Among the institutional training grants funded by NIAAA, our training program is one of three devoted to genetics of alcoholism and related biological problems. The main focus of research training is on the genetic, biological and molecular basis of high alcohol-seeking behavior. Major topics of research include: neuronal mechanisms responsible for the reinforcing effects of low-dose ethanol; the biological factors that mediate the aversive effects of high-dose ethanol; the development of acute tolerance to the aversive effects of ethanol; the relationship of polymorphism of alcohol dehydrogenase, aldehyde dehydrogenase and cytP450llE1 to the alcohol flush reaction, alcohol elimination rate, and individual susceptibility to alcoholism and alcohol- related pathology; the genetics of alcohol preference in selectively bred rat and mouse lines (P/NP, HAD/LAD and HAP/LAP lines); studies of factors that regulate the expression of genes relevant to alcoholism; and studies in twins and in family history positive and negative subjects on the heritability of acute responses to alcohol and alcohol tolerance. Other topics of interest include: structure and function of alcohol dehydrogenases and aldehyde dehydrogenases; the syntheses of ethylcocaine and fatty acid ethyl esters and their implications; trait and state markers of alcohol abuse and alcoholism; effect of alcohol on lipoprotein metabolism; fetal alcohol syndrome; and structure and function studies on serotonin and opioid receptors. One major characteristic of our training program is the long history of collaboration with both MDs and PhDs in research and research training and the involvement of multiple scientific disciplines (enzymology, molecular biology, neurochemistry, neuropharmacology, neurophysiology, psychology, behavioral genetics etc) in collaborative research. A number of important resources are available to foster research training at the Indiana University School of Medicine: the selective bred P/NP and HAD/LAD rat lines that differ in alcohol preference, a large collection of DNA samples extracted from different human populations relevant for genetic studies of alcoholism and alcohol-related end-organ injuries, the availability of several twin panels including the Indiana University Twin Panel, an NIAAA-funded Alcohol Research Center (Molecular Biology Core, Animal Production Core, Structural Biology Core, Human Genetics and Database Core), a Program Project grant on "Neurobiology and Genetics of Alcohol-Seeking Behavior", and the participation as a coordinator center for the "Collaborative Studies on the Genetics of Alcoholism (COGA)." The trainees will include four predoctoral and four postdoctoral fellows to be supported each fiscal year. Special efforts will be made to recruit scientifically-inclined MDs from the Departments of Medicine and Psychiatry. Training will be through an apprenticeship mode but seminars, research conferences and hands-on method courses are amply available.